DESCRIPTION: The current proposal is for a Scientist Development award to Sheila Vrana, Ph.D. to investigate the role of dopamine receptor subtypes in animal behavior using in vivo administered antisense oligonucleotides designed to reduce the level of receptor expression that may yield insights into their role(s) in cocaine self- administration. The applicant has received prior training in autonomic pharmacology, neuropharmacology, and molecular biology. She wishes now, under the guidance of Dr. Herman Samson as preceptor, to enhance her training in behavioral measures relevant to drug abuse research and apply her background in molecular biology to explore the molecular foundations of behavioral responses. The present proposal will interweave the Candidate's talents with other investigators in drug abuse research at Bowman Gray School of Medicine, particularly those associated with the Center for Neurobiological Investigation of Drug Abuse. During the course of her investigations, the Candidate seeks to learn behavioral techniques related to the study of drugs as reinforcement as well as other pharmacologic/molecular tools applicable to her analysis including receptor autoradiography, in vivo microdialysis, stereotaxic surgical techniques, HPLC techniques, and other recombinant DNA approaches. Her central hypotheses are that specific dopamine receptor subtypes mediate cocaine self-administration, that alteration in expression of these subtypes may be linked to compensatory changes in additional subtype gene and protein expression, and that reductions of expression in specific receptor subtypes results in altered release of synaptic dopamine in vivo.